Improved method for preparing acyloxy enamine
阅读说明：本技术 一种用于制备酰氧基烯胺的改进方法 (Improved method for preparing acyloxy enamine ) 是由 戴乐 彭坤 张磊 于 2020-04-29 设计创作，主要内容包括：本发明提供了一种用于制备酰氧基烯胺的改进方法。与现有技术相比,本发明的方法更容易以一锅法进行操作并提供更高的产率。另外,本发明的方法可以在温和的条件下(在室温下)进行,避免了任何盐,因此是环境友好的。(The present invention provides an improved process for the preparation of acyloxyenamines. The process of the present invention is easier to operate in a one-pot process and provides higher yields than the prior art. In addition, the process of the present invention can be carried out under mild conditions (at room temperature), avoiding any salts and is therefore environmentally friendly.)
1. A one-pot process for preparing a compound of formula (I):
Which comprises the following steps:
placing a compound of formula (II), a compound of formula (III), and an acid of formula (IV) in a pot for reaction in the presence of a first solvent and a second solvent to produce a compound of formula (I),
wherein:
R1and R2May independently be H; or lower alkyl or aryl, optionally substituted with one or more small substituents; or together with the nitrogen to which they are attached form a heterocyclic ring, optionally substituted with one or more small substituents;
R3can be H; or lower alkyl or aryl, optionally substituted with one or more small substituents;
e may be C ≡ N or C (═ O) R ', where R' is H, lower alkyl, lower alkoxy, aryl or heterocycle, optionally substituted with one or more small substituents;
R4and R4' may be the same or different and may independently be H, or lower alkyl or aryl, optionally substituted with one or more small substituents;
R5and R6May independently be H, or lower alkyl or aryl optionally substituted with one or more small substituents;
r may be one or more selected from H, -NO2OH, lower alkyl, lower alkoxy and halogen.
2. The one-pot process of claim 1 wherein R1And R2Independently H, or methyl, ethyl, phenyl or benzyl, optionally substituted with one or more small substituents; or together with the nitrogen to which it is attached form a pyrrolidine, piperidinyl or morpholinyl group, optionally substituted with one or more small substituents.
3. The one-pot process of claim 1 wherein R3Is H or methyl or ethyl.
4. The one-pot process of claim 1, wherein E is C ≡ N or C (═ O) R ', where R' is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl, benzyl, furan, thiophene, pyridine, or naphthyl, optionally substituted with one or more small substituents.
5. The one-pot process of claim 1 wherein R4And R4' is independently H, or methyl, ethyl, propyl, isopropyl, phenyl, or benzyl optionally substituted with one or more small substituents.
6. The one-pot process of claim 1 wherein R5Independently H, or methyl, ethyl, phenyl or benzyl optionally substituted with one or more small substituents.
7. The one-pot process of claim 1 wherein R6Independently H, or methyl, ethyl, phenyl or benzyl optionally substituted with one or more small substituents.
8. The one-pot process of claim 1, wherein R is H, halogen, methyl, ethyl, methoxy, ethoxy, and/or-NO2。
9. The one-pot process of claim 1 wherein:
R1and R2Independently is H or methyl;
R3Is H or methyl;
e is C ≡ N or C (═ O) R ', where R' is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl, benzyl, furan, thiophene, pyridine, or naphthyl;
R4and R4' is independently H, methyl, ethyl, propyl, isopropyl, phenyl or benzyl;
R5is H, methyl or phenyl;
R6is H, methyl, ethyl, propyl, isopropyl, phenyl or benzyl; and
r is H or-NO2。
10. The one-pot process of claim 1 wherein:
R1and R2Independently H, methyl, ethyl, phenyl, benzyl, or together with the nitrogen to which they are attached form a pyrrolidine, piperidinyl, or morpholinyl group;
R3is H or methyl or ethyl;
e is C ≡ N or C (═ O) R ', where R' is H, methoxy or ethoxy;
R4and R4' is independently H, methyl, ethyl, phenyl or benzyl;
R5is H, methyl or phenyl;
R6is H, methyl, ethyl, phenyl or benzyl; and is
R is H or NO2。
11. The one-pot process of claim 1 wherein R6And R4、R4' or R5The same is true.
12. The one-pot process of claim 1 wherein R4、R5And R6Are the same.
13. The one-pot process of claim 1 wherein R4、R4’、R5And R6Are the same.
14. The one-pot process of any one of claims 1-13, wherein the compound of formula (III) is added in an amount of 0.6 to 2.0 moles, preferably 0.8 to 1.5 moles, more preferably 1.0 to 1.3 moles, per 1 mole of the compound of formula (II).
15. The one-pot process according to any of claims 1 to 13, wherein the acid of formula (IV) is any organic acid, preferably a strong organic acid, more preferably an organic acid with a pKa ≤ 4.80, such as formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, iodoacetic acid, glycolic acid, 2-chloropropionic acid or 3-chloropropionic acid, lactic acid, glyceric acid, benzoic acid, m-hydroxybenzoic acid and dihydroxybenzoic acid.
16. The one-pot process of any one of claims 1 to 13, wherein the compound of formula (IV) is used in an amount of 1 to 20 moles, preferably 2 to 15 moles, more preferably 2.5 to 10 moles per 1 mole of the compound of formula (II).
17. The one-pot process of any one of claims 1-13, wherein the first solvent is any protic solvent or mixtures thereof, such as alcohols, e.g. methanol, ethanol, n-butanol, isopropanol and 2,2, 2-Trifluoroethanol (TFE); organic acids such as formic acid and acetic acid; hexafluoroisopropanol (HFIP), and water, and mixtures thereof.
18. The one-pot process of any one of claims 1-13, wherein the first solvent is added in an amount of 1L to 20L, preferably 2L to 15L, more preferably 5L to 10L, per 1 mole of the compound of formula (II).
19. The one-pot process of any one of claims 1-13, wherein the second solvent is any aprotic solvent or mixture thereof, such as acetone, ethyl acetate, butyl acetate, Tetrahydrofuran (THF), Dichloromethane (DCM), Dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), dimethyl carbonate (DMC), methyl tert-butyl ether (MTBE), nitromethane, nitroethane; and cyclic carbonates such as Ethylene Carbonate (EC), Propylene Carbonate (PC), Butylene Carbonate (BC); and mixtures thereof.
20. The one-pot process of any one of claims 1-13, wherein the second solvent is added to the pot for reaction after complete consumption of the starting compound of formula (II) or compound of formula (III).
Technical Field
The present invention relates to an improved process for the preparation of acyloxyenamines.
Background
Oxazole compounds represent a large class of heterocyclic aromatic organic compounds. Due to the biological activity and its use as intermediates for the preparation of new biomaterials, oxazole compounds have become increasingly important. The broad biological activities of oxazole compounds include anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, antitubercular, muscle relaxant and HIV inhibitor activity. Furthermore, oxazole derivatives are important intermediates for the preparation of biological compounds such as vitamin B6.
Various methods have been developed for the preparation of oxazole compounds. An attractive approach is the direct cyclodehydration of acyloxyenamines, since acyloxyenamines have been introduced into the earlier N-atom and provided the carboxylic acid. (see Xin Liu et al, org. lett., vol 14, vol 21, 2012).
It is reported that acyloxyalkenamides can be synthesized by intermolecular oxidative coupling of enamine compounds with carboxylic acids using iodosobenzene (iodosobenzene) as an oxidizing agent. However, the oxidant iodosobenzene is extremely flammable and poses an explosion hazard. In addition, the oxidant iodosobenzene is insoluble in the solvent, thus causing instability in the yield of the process. (see Xin Liu et al, org. lett., vol 14, vol 21, 2012).
One of the improved processes is the use of phenyliodide (III) diacetate (PIDA) as an oxidant in TFE as a solvent. The improved process can be carried out under mild reaction conditions (room temperature, metal free and open flask) and is characterized by a wide substrate range. However, this process is only suitable for producing acetylenamines from PIDA as the oxidant and does not produce other acyloxyenamines, such as formyl or benzoylenamines, in high yields. (see Fei Wang et al, org. Lett.2018, 20, 1256-one 1260)
Therefore, there is still a need for further improved processes for the preparation of acyloxyenamines in industry.
Disclosure of Invention
The present invention provides a further improved process for the preparation of acyloxyalkenylamine compounds. The process of the present invention is easier to operate in one pot and provides higher yields than the prior art described above. In addition, the process of the present invention can be carried out under mild conditions (at room temperature), avoiding any salts and is therefore environmentally friendly.
Detailed Description
Specifically, the present invention provides a one-pot process for preparing acyloxyalkenylamine compounds of formula (I).
Which comprises the following steps:
placing a compound of formula (II), a compound of formula (III), and an acid of formula (IV) in a pot for reaction in the presence of a first solvent and a second solvent to produce a compound of formula (I),
wherein:
R1and R2May independently be H; or lower alkyl or aryl, optionally substituted with one or more small substituents; or together with the nitrogen to which they are attached form a heterocyclic ring, optionally substituted with one or more small substituents;
R3can be H; or lower alkyl or aryl, optionally substituted with one or more small substituents;
e may be C ≡ N or C (═ O) R ', where R' may be H, lower alkyl, lower alkoxy, aryl or heterocycle, optionally substituted with one or more small substituents;
R4and R4' may be the same or different, and may independently be H, or lower alkyl or aryl optionally substituted with one or more small substituents;
R5and R6May independently be H, or lower alkyl or aryl optionally substituted with one or more small substituents;
r may be one or more selected from H, -NO 2OH, lower alkyl, lower alkoxy and halogen.
In the present invention, the term "lower alkyl" as used means C1-C10Alkyl, i.e. branched or unbranched, cyclic or acyclic, saturated radicals containing from 1 to 10 carbon atomsAnd hydrocarbons. Preferably, "lower alkyl" is C1-C6Alkyl groups including, but not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, "lower alkyl" is methyl or ethyl.
In the present invention, the term "aryl" is used to mean an aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthyl.
In the present invention, the term "lower alkoxy" is used to refer to a structure represented by (lower alkyl) -O-, wherein "lower alkyl" is as defined above.
In the present invention, the term "heterocycle" is used to refer to aromatic and non-aromatic mono-and fused rings containing from 3 to 10, preferably 5 or 6 ring atoms, at least one of which is oxygen, nitrogen, sulfur or a combination thereof. Examples of heterocycles include, but are not limited to, furan, pyrrolidine, pyridyl, thiophene, piperidyl, morpholinyl, piperazine, quinoline, indoline, and indolyl.
In the present invention, the term "halo" or "halogen" is used to refer to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably to Cl or Br.
In the present invention, the term "small substituent" is used to mean lower alkyl, lower alkoxy, hydroxy (OH), halogen, NH2Or NO2。
Preferably, R1And R2Independently is H; or lower alkyl, phenyl or benzyl, optionally substituted with one or more small substituents; or together with the nitrogen to which they are attached form a pyrrolidine, piperidinyl or morpholinyl group, optionally substituted with one or more small substituents.
More preferably, R1And R2Independently is H; or C1-C6Alkyl, phenyl or benzyl, optionally substituted with one or more small substituents; or withThe attached nitrogens taken together form a pyrrolidine, a piperidinyl or a morpholinyl group, optionally substituted with one or more small substituents. More preferably, R1And R2Independently H, or methyl, ethyl, phenyl or benzyl, optionally substituted with one or more small substituents; or together with the nitrogen to which it is attached form a pyrrolidine, piperidinyl or morpholinyl group, optionally substituted with one or more small substituents. More preferably, R1And R2Independently is H; or methyl, ethyl, phenyl or benzyl, optionally substituted with one or more small substituents. Most preferably, R 1And R2Independently H or methyl.
Preferably, R3Is H or lower alkyl optionally substituted with one or more small substituents. More preferably, R3Is H or C optionally substituted with one or more small substituents1-C6An alkyl group. More preferably, R3Is H or methyl or ethyl. Most preferably, R3Is H or methyl.
Preferably, E is C ≡ N or C (═ O) R ', where R' is H, lower alkyl, lower alkoxy, phenyl, benzyl, furan, thiophene, pyridine or naphthyl, optionally substituted with one or more small substituents. More preferably, E is C ≡ N or C (═ O) R ', where R' is H, C1-C6Alkyl radical, C1-C6Alkoxy, phenyl, benzyl, furan, thiophene, pyridine, or naphthyl, optionally substituted with one or more small substituents. More preferably, E is C ≡ N or C (═ O) R ', where R' is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl, benzyl, furan, thiophene, pyridine or naphthyl, optionally substituted with one or more small substituents. More preferably, E is C ≡ N or C (═ O) R ', where R' is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, methoxy, ethoxy, propoxy, or phenyl, benzyl. Most preferably, E is C ≡ N or C (═ O) R ', where R' is H, methoxy, ethoxy or benzyl.
Preferably, R4And R4' is independently H, or lower alkyl, phenyl or benzyl optionally substituted with one or more small substituents. More preferably, R4And R4' is independently H, or C optionally substituted with one or more small substituents1-C6Alkyl, phenyl or benzyl. More preferably, R4And R4' is independently H, or methyl, ethyl, propyl, isopropyl, phenyl, or benzyl optionally substituted with one or more small substituents. More preferably, R4And R4' is independently H, methyl, ethyl, phenyl or benzyl. Most preferably, R4And R4' is independently H, methyl, ethyl or phenyl.
Preferably, R5Is H, or lower alkyl, phenyl or benzyl optionally substituted with one or more small substituents. More preferably, R5Independently is H, or C optionally substituted with one or more small substituents1-C6Alkyl, phenyl or benzyl. More preferably, R5Independently H, or methyl, ethyl, phenyl or benzyl optionally substituted with one or more small substituents. Most preferably, R5Independently H, methyl, ethyl or phenyl.
Preferably, R6Is H, or lower alkyl, phenyl or benzyl optionally substituted with one or more small substituents. More preferably, R 6Independently is H, or C optionally substituted with one or more small substituents1-C6Alkyl, phenyl or benzyl. More preferably, R6Independently H, or methyl, ethyl, phenyl or benzyl optionally substituted with one or more small substituents. Most preferably, R6Independently H, methyl, ethyl or phenyl.
Preferably, R is selected from H, -NO2、OH、C1-C6Alkyl radical, C1-C6Alkoxy or halogen. More preferably, R is H, halogen, methyl, ethyl, methoxy, ethoxy and/or-NO2。
In one embodiment, R1And R2Independently is H or methyl；R3Is H or methyl; e is C ≡ N or C (═ O) R ', where R' is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, propoxyphenyl, benzyl, furan, thiophene, pyridine, or naphthyl; r4And R4' is independently H, methyl, ethyl, propyl, isopropyl, phenyl or benzyl; r5Is H, methyl or phenyl; r6Is H, methyl, ethyl, propyl, isopropyl, phenyl or benzyl; and R is H or NO2。
In another embodiment, R1And R2Independently H, methyl, ethyl, phenyl, benzyl, or together with the nitrogen to which they are attached form a pyrrolidine, piperidinyl, or morpholinyl group; r 3Is H or methyl or ethyl; e is C ≡ N or C (═ O) R ', where R' is H, methoxy or ethoxy; r4And R4' is independently H, methyl, ethyl, phenyl or benzyl; r5Is H, methyl or phenyl; r6Is H, methyl, ethyl, phenyl or benzyl; and R is H or NO2。
In the process of the present application, the compound of formula (III) may be added in an amount of 0.6 to 2.0 moles, preferably 0.8 to 1.5 moles, more preferably 1.0 to 1.3 moles per 1 mole of the compound of formula (II).
In the process of the present invention, the acid of formula (IV) may be any organic acid. Preferably, it is a strong organic acid, more preferably an organic acid with a pKa ≦ 4.80. Examples of organic acids having a pKa ≦ 4.80 include, but are not limited to, formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, iodoacetic acid, glycolic acid, 2-chloropropionic acid or 3-chloropropionic acid, lactic acid, glyceric acid, benzoic acid, m-hydroxybenzoic acid, and dihydroxybenzoic acid. The acid of formula (IV) used in the process of the present invention may be used in an amount of 1 to 20 moles, preferably 2 to 15 moles, more preferably 2.5 to 10 moles per 1 mole of the compound of formula (II).
In the process of the present application, the first solvent may be any protic solvent or a mixture thereof. Examples of suitable protic solvents include, but are not limited to, alcohols such as methanol, ethanol, n-butanol, isopropanol, and 2,2, 2-Trifluoroethanol (TFE); organic acids such as formic acid and acetic acid; hexafluoroisopropanol (HFIP), and water and mixtures thereof. Preferably, the protic solvent is TFE. The first solvent may be added in an amount of 1L to 20L, preferably 2L to 15L, more preferably 5L to 10L, per 1 mole of the compound of formula (II).
In the process of the present invention, the second solvent may be any aprotic solvent or a mixture thereof. Examples of aprotic solvents include, but are not limited to, acetone, ethyl acetate, butyl acetate, Tetrahydrofuran (THF), Dichloromethane (DCM), Dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), dimethyl carbonate (DMC), methyl tert-butyl ether (MTBE), nitromethane, nitroethane; cyclic carbonates such as Ethylene Carbonate (EC), Propylene Carbonate (PC), Butylene Carbonate (BC), and mixtures thereof. Preferably, the aprotic solvent is DCM or PC. The second solvent may be added in an amount of 20L to 80L, preferably 30L to 60L, more preferably 45L to 55L, per 1 mole of the compound of formula (II).
Preferably, the second solvent is soluble in the first solvent. More preferably, the first solvent is TFE, and the second solvent is DCM.
Preferably, the second solvent is added to the pot for reaction after the starting compound of formula (II) or compound of formula (III) is completely consumed. The consumption of starting materials in the reaction can be monitored according to techniques known in the art.
In the process of the invention, the radical R in the compounds of the formula (I)6Can be reacted with the radical R in the compounds of the formula (III) 4Or R4' or the group R in the compound of the formula (IV)5The same is true. Preferably, the group R6And R5The same is true. More preferably, the group R4、R5And R6Are the same. Further preferably, the group R4、R4'、R5And R6Are the same.
The reaction of the process of the invention can be carried out at room temperature. The obtained compound of formula (I) can be easily isolated and purified by any known method, such as distillation and column chromatography.
The starting compounds of formula (II) are commercially available or synthesized according to methods known in the art (e.g. as disclosed in org. lett.,2012,14(21), pp 5480-.
Compounds of formula (III) are commercially available or can be synthesized according to methods known in the art (e.g., as disclosed in Huaqiang Fan et al, Organic Letters, 20(24), 7929-.
Thus, the present invention provides a process that can be carried out in one pot under mild conditions. In addition, the process of the present invention avoids any salt and provides significantly improved yields.
The invention is further illustrated by the following examples.